Liver Function Tests Functions of the liver Carbohydrate and Lipid - - PowerPoint PPT Presentation

Liver Function Tests

Functions of the liver

► Carbohydrate and Lipid metabolism

• Gluconeogenesis / Glycogenolysis / Glycogenesis
• Cholesterol and triglyceride production

► Synthetic function

• Amino acids processing and formation
• Protein synthesis

► albumin, ► coagulation factors ( fibrinogen, prothrombin, V, VII, IX, X and XI), ► anticoagulants (protein C, protein S, antithrombin) ► acute phase proteins

• Bile acids ( fat digestion)
• Heparin (anti-coagulant)
• Hormone production

► somatomedins (promote growth in bone, soft tissues) ► angiotensinogen ► ILF-1 ► thrombopoietin

Functions of the liver

► Storage Capacity

• Glycogen, vitamins A, B12, D, E, K, iron, copper

► Metabolism of waste products / toxins

• Deamination of amino acids / Ammonia processing
• Phase 1 / Phase 2 reactions

► Immune function

• Reticulo endothelial function

►Kupffer cells

• IgA into digestive tract

Anatomy

Liver problems on the wards

► Sepsis ► Drug overdose / poisoning ► Trauma

• Accidental / Post liver resection

► Alcoholism ► Jaundice

• Hepatitis
• Cholecystitis

► Variceal bleeding 2 portal hypertension ► Spontaneous bacterial peritonitis

Liver function tests

►Confusing

• Lots of them
• Dynamic - can change rapidly
• Not specific
• When high might be normal
• When low might be bad
• When normal liver might be sick
• Involves metabolic pathways I can’t remember

Tests

►LFTs – enzymes AST ALT GGT ALP ►Synthetic function

• Total protein / Albumin / prothrombin time

►Metabolism

• Bilirubin / glucose levels

►Markers of liver disease

• Sodium, urea, glucose, lactate, ammonia

What to do?

► History ► Examination ► Investigation ► Patterns – indicative of

disease process

M C Escher ( Dutch graphic artist : 1898 –1972), Known for mathematically inspired prints with impossible constructions, explorations of infinity, architecture, and tessellations.

Aminotransferases

►involved with amino acid metabolism ►allow transamination,

• converts an amino acid into its oxoacid by

transfer of an amino (-NH2)

• require pyridoxal phosphate as a coenzyme.

Aminotransferases

►Liver

• 2 aminotransferases
• cytoplasmic and mitochondrial

►ALT predominantly hepatic (cytosol),

(negligible in heart/muscle/kidneys)

►AST (mitochondria and cytosol) in liver,

• also in muscles (cardiac and skeletal) , kidney,

pancreas and erythrocytes

►ALT and AST are released from liver when

hepatocytes are damaged or destroyed

What to do?

► History ► Examination ► Investigation ► Patterns – indicative of

disease process

► If doubt measure

another enzyme e.g. CK / TN

► Organise imaging/test

ALT - Alanine Transaminase

► Enzyme

• Converts amino acid into pyruvate

► Predominantly in liver,

• also in skeletal muscle, kidneys and

heart

► Located in cytosol

• Spilled out into plasma as liver cells

die

• Usually higher than AST
• Good marker of liver inflammation
• Can be normal in sick liver
• In alcoholic liver disease usually

lower than AST

ALT > AST (normal) AST > ALT ETOH disease

ALT normal in sick liver

ALT and disease

► Very high levels ( upto x50 normal)

• Severe necrosis, severe viral or drug induced hepatitis

► Moderately high levels

• EBV, chronic hepatitis, cholestasis, early or improving

acute viral hepatitis, CCF with hepatic congestion

► Slight-to-moderate elevations

• (usually with higher increases in AST levels)
• insult producing acute hepatocellular injury, eg active

cirrhosis, and drug-induced or alcoholic hepatitis

► Marginal elevations

• acute MI, (hepatic congestion or ALT from heart)

AST

► Two isoenzymes are present In humans:

• GOT 1 - cytosolic red blood cells / muscles cytoplasm / kidneys
• GOT 2 - liver mitochondria and cytosol

ALT and AST

►In general,

• increases in AST and ALT are higher with viral
• r toxin hepatitis than with biliary obstruction
• in viral hepatitis levels may rise upto 14 days

before jaundice

►Cholestasis will increase ALT and AST when

associated with hepatocellular death

Typical AST/ALT Values in Disease

Aminotransferases often normal in cirrhosis. In uncomplicated alcoholic hepatitis, AST normally less than 500 U per L The highest peak aminotransferase values are found in patients with acute ischemic or toxic liver injury.

Rules of thumb

1.

The higher the AST : ALT ratio, greater likelihood alcohol contributing to abnormal LFTs

• In alcohol the ratio is normally 2:1
• elevated AST : ALT ratio in alcoholic liver disease results from

the depletion of vitB6 (pyridoxine), needed as a cofactor

2.

In the absence of alcohol intake, increased AST : ALT ratio often found in patients with cirrhosis

3.

ALT level > 500 IU/L unlikely to be just alcoholic liver disease

4.

AST:ALT ratios are suggestive of certain conditions but ratio cannot be totally relied on

ALP – alkaline phosphatase

► Enzyme which dephosphorylates substrates

• Eg proteins, nucleotides, in an alkaline environment
• May have role in regulating biliary secretions

► Found in all tissues

• predominantly liver ( bile duct 55%),
• bone ( osteoblasts 45%),
• gut (5%) / kidney / placenta

► Isoforms exist –

• ALP I intestinal 5%
• ALP L tissue non specific (Liver/Kidney/Bone)
• ALP P placental

Elevated ALP ? normal = 20 – 140 iu / l

► differentiate source ► are other LFTs elevated including bilirubin?

• (electrophoresis / heat exposure) bone burns, liver

lasts

► Higher ALP levels may be due to:

• Biliary obstruction / Liver disease
• Bone disease - Healing fracture / Osteoblastic bone

tumors / Osteomalacia / Paget's / Rickets

• Hyperparathyroidism
• Leukemia / Lymphoma
• Sarcoidosis
• Fatty meal ingestion (blood type O or B)

Obstructive picture

Gamma glutaryl transferase

► Catalyst for transport of gamma glutaryl group from

glutathione found at cell membranes

► Actual role unclear BUT

• Glutathione - free radical scavenger involved in detoxification

► Found in hepatocytes and biliary epithelial cells ► Used as “ESR” of the liver ► Increase in alcoholics and obstructive biliary disease

• unclear why elevated in alcoholics
• possible induction of enzymes / leakage from cells / increased
• xidative stress
• may be elevated on its own in drinkers

Alcoholic hepatitis

Obstructive picture

Jaundice

Bilirubin

► Processing involves three steps

• 1. Absorption
• 2. Conjugation
• 3. Excretion
• Rate limiting step is excretion
• Often conjugated form in liver diseases

Causes of jaundice

► Unconjugated Bilirubinaemia

• < 20% bilirubin is conjugated

1) Overproduction -

► Haemolysis / rhabdomyolysis / ineffective erythropoiesis

2) Decreased hepatic conjugation -

► Heme enters liver, converted to bilirubin, but not conjugated ► Bilirubin builds up blood and is filtered by the kidneys into urine

• Causes

1.

Gilberts syndrome (mild drop glucuronyl transferase)

2.

Crigler - Najar syndromes

3.

Hepatitis - viral and drugs

Causes of jaundice

► Conjugated Bilirubinaemia

• > 50% bilirubin is conjugated

► Impaired intrahepatic secretion

• Hepatocellular disease
• Sepsis
• Cholestasis of pregnancy
• Drug induced IVN / Clavulinic acid / flucloxacillin / carbamazepine

OCP / erythromycin

• Infiltrative processes (amyloid / sarcoid)

► Impaired extraheptic clearance

• Mechanical obstruction ( stones/tumour)

Gilberts Syndrome

Acute Liver failure

►Hyperacute

• onset of encephalopathy <7 days of jaundice

►Acute

• encephalopathy within 8 – 28 days of jaundice

►Subacute

• encephalopathy within 4 – 26 weeks

O’Grady, Lancet 1993

Causes of acute liver failure

►Viral ►Drugs / Toxins ►Vascular events ►Others

• pregnancy / Wilsons / lymphoma / trauma /

heat stroke

Overdoses / Poisoning

Hyperacute Liver Failure - Mushrooms

Paracetamol toxicity in chronic liver disease

Paracetamol toxicity

Trauma

Lactate

►Type A - Hypoxic

• Reduced oxygen / perfusion –

►Liver failure / sepsis

►Type B – Nonhypoxic

• 1) disease states : Sepsis / Liver disease /

thiamine deficiency

• 2) drugs – metformin / ethanol / paracetamol
• 3) metabolic disorders – mitochodria eg G6PD /

MELAS /

Mitochondrial disease - MELAS

mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes

Prothrombin time

►does not become abnormal until more than

80% of liver synthetic capacity is lost

►PT a relatively insensitive marker of liver

dysfunction

• only based on manufacture of clotting factors

and dependent on vit K stores

►Often useful for following liver function in

patients with acute liver failure

Liver failure and prothrombin time

Liver failure and INR

Hepatic encephaolpathy

Albumin

►Production 10-25 g/day (upto x2 increase)

• T1/2 20 days
• Albumin pool approx 5g/kg
• 60% (210g)interstitial space
• 40% (140g) - intravascular
• 70% oncotic pressure due to albumin
• 7% (7g) intravascular leeks out each hour

Albumin - Functions

►Transports fatty acids ►Binds bilirubin ►Binds drugs and hormones ►Scavenges free radicals ►Buffers pH

Hypoalbuminaemia

► Reduced production

• Liver disease : cirrhosis and acute liver failure
• Malnutrition / Malabsorption
• Chronic renal failure
• Disseminated cancer
• Acute disease states (-ve acute-phase protein)

► Increased Loss

• Excess excretion kidneys (nephrotic syndrome)
• Excess loss in bowel (protein losing enteropathy)
• Burns / Necrotising fasciitis (absence of skin barrier)
• Pancreatitis / Sepsis

► Haemodilution (pregnancy), ► Increased Intersitial deposition

• Increased vascular permeability (sepsis)
• Decreased lymphatic clearance)

A - I of liver problems

► A - auto immune / alcohol ► B - hep B / Biliary disorder / blirubin problem / blockage ► C - hep c / cholestasis ► D - drugs / toxins ► E - ethanol ► F - fatty liver ► G - growths ie cancers ► H - haemodynamic disorder, CCF / cardiac tamponade,

hypoxia

► I - Iron and others ( haemo. Wilsons a1 anti trypsin)

Surgical Sieve

► VITAMIN C,D,E,F

• V

: Vascular

• I

: Infective /Inflammatory

• T

: Trauma

• A

: Auto-immune

• M

: Metabolic

• I

: Idiopathic / Iatrogenic

• N

: Neoplastic

• C

: Congenital

• D

: Degenerative/Developmental

• E

: Endocrine/Environmental

• F

: Functional

Questions ?